Use of organic superbases and temperature effects for the development of reversible protic amino acid salts

Article abstract of DOI:10.1055/s-0033-1339880

Novel reversible organic salts based on amino acids in the presence of organic superbases [1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and tetramethylguanidine (TMG)] have been prepared. An optimized acid-base reaction methodology allowed the preparation of novel protic amino acid salts with improved water-solubility profiles and unexpected phase behavior. Complementary differential scanning calorimetry (DSC) and thermal ¹H NMR analysis indicated that a phase separation between water and amino acid salt occurs and that the process is reversible, depending upon temperature and the selected organic superbase. These studies open the possibility for tuning miscibility and ionicity of organic salts as well as development of reversible protic chiral ionic liquids or molten salts. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339880

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cluster
Use of Organic Superbases and Temperature Effects for the Development of
Reversible Protic Amino Acid Salts
Development of Reversible Protic Amino Acid Salts
Gonçalo V. S. M. Carrera, Alexandra Costa, Manuel Nunes da Ponte, Luis C. Branco*
REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal
Fax +35(121)2954461; E-mail: l.branco@fct.unl.pt; E-mail: mnponte@fct.unl.pt
Received: 31.07.2013; Accepted after revision: 09.09.2013
A different type of carbonate- and carbamate-based PIL
Abstract: Novel reversible organic salts based on amino acids in
resulting from reaction of alcohols7 or amines8 with CO2
the presence of organic superbases [1,8-diazabicyclo[5.4.0]undec-
in the presence of an organic superbase are even more
prone to reversibility under moderate temperatures, asso-
7-ene (DBU) and tetramethylguanidine (TMG)] have been pre-
pared. An optimized acid–base reaction methodology allowed the
preparation of novel protic amino acid salts with improved water- ciated with flushing by an inert gas to remove CO2 from
solubility profiles and unexpected phase behavior. Complementary
the system.
differential scanning calorimetry (DSC) and thermal 1H NMR anal-
From another perspective, amino acids can be used to con-
ysis indicated that a phase separation between water and amino acid
struct chiral ionic liquids (IL), allowing their use as
anionic9 or cationic species.10 Additionally, the choice of
the side chain of amino acids can open new perspectives
for the applications of their corresponding PILs as molten
salts, in particular as chiral solvents, shift reagents, enan-
tioselective catalysts,11 in cellulose dissolution,12 electro-
chemistry,13 or as solvatochromic probes.14 Ohno and
Fukumoto reported that an amino acid based IL, whilst
forming two phases when in contact with water at room
temperature, can mix completely with water at lower tem-
peratures.12 Another example, based on the polyethylene
oxide/water system, shows the same principle of weaken-
ing hydrogen bonding incrementally with temperature
leading to phase separation.15
salt occurs and that the process is reversible, depending upon tem-
perature and the selected organic superbase. These studies open the
possibility for tuning miscibility and ionicity of organic salts as well
as development of reversible protic chiral ionic liquids or molten
salts.
Key words : amino acids, green chemistry, ionic liquids, cations,
protonation
Protic ionic liquids (PIL) and molten salts can be modified
in order to tune some physicochemical properties such as
melting point, solubility, conductivity, and polarity. Not
only the pKa (difference between acid and base compo-
nents) but also the ability to form a hydrogen bond,1 the
coulombic, π–π, and permanent/induced dipolar interac-
tions control the behavior of the PIL. An appropriate
choice of acid and base is used to optimize the PIL for spe-
cific tasks in different scientific topics such as organic
synthesis, analytical and biological applications, for ex-
ample, fuel cells, explosives or as lubricants,2 among oth-
ers.
NMR spectroscopy can be used to evaluate the hydrogen
bond strength,1 relative degree of aggregation,16 proton
exchange,17 and degree of ionicity,18 in particular how
these parameters vary with temperature. Such studies
should be valuable for the optimization of processes such
as control of miscibility between two hydrogen-bond-
based solvents in extractions, tuning of ionic strength, sol-
ubilization or selective precipitation, and in potentiomet-
ric applications.
Organic superbases, an established class of compounds,
open diverse perspectives in the field of organic synthesis
relating to their versatility for the application as reagents,
catalysts, or even solvents. Nitrogen and phosphorous are
the key elements that control and define the pKa of such
compounds. In order to illustrate this fact, the order of ba-
sicity increases with the number of conjugated nitrogen
atoms in the molecule (amine < amidine < guanidine).3
The literature describes several examples of superbases
such as the amidine (1,8-diazabicyclo[5.4.0]undec-7-ene,
DBU)4 or the guanidine (tetramethylguanidine, TMG)
systems,3,5 used in the construction of PIL. As previously
noted,4,6 increasing temperature can lead to a decrease in
the ionicity of PIL by reversible proton exchange.
In the present work, the acid–base reaction between an
amino acid (glycine, L-alanine, L-phenylalanine, and D,L-
tryptophan) and an organic superbase (DBU and TMG)
have been evaluated in order to obtain their respective
salts. The physical, chemical, and thermal properties of
these salts including the variation of phase behavior were
studied for all the prepared PILs. Additionally, a detailed
temperature-dependent 1H NMR study was performed for
two representatives in order to illustrate the importance of
temperature in the proton disposition within the system.
The selected amino acid and organic superbase were com-
bined to result in equivalent cation/anion (1:1) composi-
tion. Glycine, L-alanine, L-phenylalanine, and D,L-
tryptophan were selected as representative amino acids
and reacted with DBU and 1,1,3,3-tetramethylguanidine
(TMG) as representative organic superbases (Scheme
1).25–27
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Advanced online publication: 18.10.2013
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DOI: 10.1055/s-0033-1339880; Art ID: ST-2013-D0732-C
© Georg Thieme Verlag Stuttgart · New York

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G. V. S. M. Carrera et al.
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O
O
NH
R1
R1
N
OH
+
superbases (SB)
SB
SBH
O
N
N
NH2
N
NH2
DBU
TMG
Scheme 1 Acid–base reaction between selected amino acids and organic superbases: glycine (R1 = H), L-alanine (R1 = Me), L-phenylalanine
(R1 = Bn), and D,L-tryptophan (R1 = methylindolyl).
+
Table 1 summarizes the yields and some of the properties sity overtone bands attributed to the NH3 group of the
of the salts thus prepared. In general, high isolated yields amino acid at 2623 and 2169 cm–1 and a strong band at
(89–100%) were achieved except in the cases of 1647 cm–1 for protonated DBU. Furthermore,
[TMGH][Gly] and [TMGH][(L)-Ala]. In these cases a sig- [DBUH][Gly] demonstrates a higher water affinity than
nificant discrepancy between amino acid (anion) and su- the parent amino acid showing and intense broad absorp-
perbase (cation) when compared with the expected 1:1 tion centered at 3442 cm–1 attributed to the presence of
proportion was observed after solvent evaporation. In or- water. Equally, [DBUH][(L)-Ala]29 showed a similar
der to explain this fact it is important to consider that, chemical shift for the carbons adjacent to the amidinium
when a reagent is removed from an acid–base chemical group of DBU, again attributed to the proton interaction
equilibrium, the correspondent equilibrium is shifted to between the amino acid and DBU.
replace that component (in this case conversion of
The [DBUH][(L)-Ala] was obtained as homogeneous sol-
TMGH+ into TMG). TMG possess a vapor pressure of 30
id at room temperature but it became heterogeneous at
Pa at 20 °C, and the acid–base reaction of TMG with the
temperatures over 35 °C. The broad absorption centered at
glycine and alanine appears either to be incomplete or the
3397 cm–1 in the FTIR spectrum and the high water affin-
proton is hydrogen bonded between the amino acid and
ity (Table 1) are indicative that a considerable quantity of
the organic superbase. In contrast, the salts [TMGH]-
water is present in the product and that, on heating, hydro-
[(L)-Phe] and [TMGH][(D,L)-Trp] do not appear to be-
gen bonding becomes weaker such that the mixture be-
have in the same manner, and the 1:1 proportion between
comes heterogeneous.12
amino acid and superbase was retained after solvent evap-
The 1H NMR spectrum of [DBUH][(L)-Phe] is indicative
oration. A possible explanation for this fact should be related
that the α-protons are more shielded (δ = 3.89 vs. δ = 3.99
with the additional π–π interactions between the L-phenyl-
ppm21) than in parent amino acid. Regarding
[TMGH][(L)-Phe], α- and β-protons of the anion are even
more shielded in relation to the zwitterionic L-phenylala-
nine, indicating that TMG is a more effective superbase
than DBU for proton transfer. These observations can be
corroborated by FTIR spectra of [DBUH][(L)-Phe]30 and
[TMGH][(L)-Phe].31 Whereas in the former, the low-
intensity overtone band at 2123 cm–1 is indicative of the
alanine and D,L-tryptophan with TMG.19
The loss of TMG from [TMGH][Gly] and [TMGH]-
[(L)-Ala] raises the question of the true nature of the inter-
action between the amino acid and the superbase. Accord-
ing to MacFarlane et al.,20 a pKa difference of 4 is enough
for a complete proton transfer. In the case of TMG, the
+
pKa difference between it and the NH3 group of the ami-
no acids is around 4 (slightly lower when DBU is used).
In contrast to TMG, however, the 1:1 proportion was pre-
served in all cases where DBU was used as the organic su-
perbase – possibly explained by high boiling point of
DBU.
In this context, it is possible to propose that, in these situ- cm–1, respectively.
ations, the cation and anion are not well defined; but in-
+
existence of the NH3 group of the amino acid, the virtual
absence of a corresponding absorption in the TMG salt
highlights the complete proton transfer between L-phenyl-
alanine and TMG. In both cases DBU and TMG were pro-
tonated as indicated by intense bands at 1646 and 1609
In the case of the (D,L)-tryptophan-derived salts
stead proton sharing by hydrogen bonding might be
occurring. This hypothesis is supported by NMR and
FTIR data. There is a significant difference in chemical
shift from δ = 3.57 ppm for the α-proton of zwitterionic
glycine21 to δ = 3.14 ppm for the equivalent proton in
[DBUH][Gly]28 in the respective 1H NMR spectra in D2O,
indicating a higher degree of shielding as a result of a
hydrogen-bonding interaction between the amino acid
and DBU. Additionally, the amidinium carbon in the
DBU structure is more deshielded {δ = 165.91 ppm as ex-
perimental value, observed for [DBUH][Gly] in D2O}
when compared with the calculated value (δ = 157.3
ppm22) as another indication that DBU is protonated. Ad-
ditionally, FTIR spectroscopy shows relatively low-inten-
{[DBUH][(D,L)-Trp]32 and [TMGH][(D,L)-Trp]33} 1H
NMR analysis indicates that, in both compounds, the
β-protons are more shielded than equivalent protons in the
parent amino acid;21 this effect being more pronounced in
[(D,L)-Trp] as with the L-phenylalanine-based salts. The
FTIR spectra indicated more intense overtone bands relat-
+
ed to the NH3 group in [DBUH][(D,L)-Trp] than in
[TMGH][(D,L)-Trp], again as expected, and a lower pro-
portion of water than with the glycine-, L-alanine-, or
L-phenylalanine-based salts according to the water affini-
ties presented in Table 1. In all the salts was observed an
increase of aqueous solubility, comparing with parent
zwitterionic amino acids.
Synlett 2013, 24, 2525–2530
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Development of Reversible Protic Amino Acid Salts
2527
Table 1 Acid–Base Reaction between Selected Amino Acids and Organic Superbases
Acid–base product
Yield
(%)a
Physical state
Transition beginning
of heterogeneity (°C)b
Water solubility
(g/L)c
[DBUH][Gly]
89
n.d.
97
heterogeneous mixture
–
–
800 (300)
–
[TMGH][Gly]d
–
[DBUH][(L)-Ala]
[TMGH][(L)-Ala]d
[DBUH][(L)-Phe]
[TMGH+][(L)-Phe–]
[DBUH+][(D,L)-Trp–]
[TMGH+][(D,L)-Trp–]
a Isolated yield.
white solid
–
35
–
900 (200)
–
n.d.
98
orange paste
brown paste
yellow solid
brown solid
68
127
85
111
200 (40)
100 (40)
7 (<6)
15 (<6)
100
100
100
b Indication of initial of transition from homogeneous to heterogeneous mixture, this heterogeneity remains over a high temperature range.
c Water solubility: solubility of original amino acid indicated in parentheses.
d Cation and anion are not in stoichiometric proportions (1H NMR analysis) due to loss of tetramethylguanidine by evaporation under reduced
pressure.
An important point of this study is related to the observa- sity decreases with the increase in temperature. Addition-
tion of the onset of temperature-dependent heterogeneity ally, it was possible to observe the conservation of the 1:1
instead of a defined melting point. Two different hypoth- proportion, (D,L)-tryptophan/superbase for both com-
eses could explain such a behavior. Normally, acid–base pounds studied, with the variation of temperature.
reactions are exothermic. Therefore, assuming that these
Considering [DBUH][(D,L)-Trp] (Figure 1), when in-
systems follow the same principle when increasing the
creasing the temperature from 30 to 70 °C, the broad res-
temperature, by Le Chatelier’s principle the equilibrium
onance corresponding to water and possibly amidine NH
will be moved towards the reagents (solid amino acid and
and amine NH2 protons (Figure 1, a) shifts to lower field,
liquid superbase). Alternatively, the presence of water in
indicating a reinforcement of hydrogen-bond interactions
the salts and the transition to heterogeneity could be a re-
or higher degree of association, in contradiction with oth-
sult of the weakening of hydrogen bonds with
er studies.12,15 With further increase in temperature to 90
temperature12,15 and consequent phase separation.
°C the trend is reversed, the band shifts once again to
To distinguish these hypotheses a differential scanning higher field, indicating that hydrogen bonding is become
calorimetry (DSC) study was performed with weaker (heterogeneity commences at 85 °C, Table 1). To
[DBUH][(L)-Ala] when an endotherm was observed start- explain this reversal of behavior, it is important to recall
ing at ~ 30 °C to 120 °C. In the subsequent heating cycles that the pKw of water decreases with temperature until ca.
the endothermic process was less pronounced. These data 250 °C at 0.1 MPa (atmospheric pressure), and in that
indicate that, in the first cycle when a considerable quan- range, the variation of pKw decreases with the increasing
tity of water was present, a phase separation between the temperature.23 In addition, the evidence that DBU is less
water and the [DBUH][(L)-Ala] occurred in the initial protonated and that (D,L)-tryptophan is more neutral at
stages. With further increase to 120 °C, water was physi- lower temperatures (Figure 1, b and c) leads to the conclu-
cally lost and, in the further heating cycles the endother- sion that the more pronounced increase in ionicity of wa-
mic effect was lessened. To confirm the water effect, the ter and DBU (Figure 1, b), in the initial stages of increase
sample was then exposed to air during 24 hours, and after in temperature (30–70 °C), is more important in strength-
that period a similar DSC study was performed. Once ening the hydrogen-bond interactions (the major energetic
again the first cycle a pronounced endothermic effect was component of hydrogen bonds is electrostatic and only a
observed when heating the sample, but this diminished small fraction is covalent24) than is the effect of direct in-
significantly in further cycles.
crease of temperature in diminishing them.
In order to investigate further the molecular interactions With further increase of temperature, increasing ionicity
responsible for such behavior, a thermal 1H NMR study of slows down, and the effect of temperature is more pro-
[DBUH][(D,L)-Trp] was performed in predried deuterated nounced in reducing directional hydrogen-bonding inter-
DMSO (Figure 1).
actions. Considering Figure 1 (d), the displacement of the
NH resonance of the secondary aromatic amine towards
higher field is indicative of a decrease in hydrogen-bond-
ing interaction with increasing temperature (the proton is
more localized on the nitrogen atom). The fact that DMSO
1
In these H NMR thermal studies it was possible to ob-
serve a steady decrease of the area of the peaks with the
increase of temperature, presumably arising because den-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2525–2530

2528
G. V. S. M. Carrera et al.
CLUSTER
is insensitive to variation of temperature as shown in Fig- melting point was observed. A combination of DSC anal-
1
ure 1 (e) is indicative that any solvent interaction with ysis with variable temperature H NMR studies indicate
[DBUH][(D,L)-Trp] is independent of temperature.
that phase separation on increasing temperature results
from weakening of hydrogen-bond interactions between
water and the salts. 1H NMR studies, [DBUH][(D,L)-Trp]/
water verified that the process was reversible. Additional-
ly, the choice of the organic superbase is the key step in
order to tune the corresponding protonation or deproton-
ation of the amino acid.
In order to verify that the system [DBUH][(D,L)-Trp] was
reversible, a comparison of two 1H NMR spectra at 70 °C
was carried out, one recorded when increasing the temper-
ature, the other recorded when decreasing the tempera-
ture. Both spectra are superimposable, indicating that the
system is reversible.
In summary, the combination of amino acids with organic
superbases has allowed the preparation of novel organic
salts in high yields with improved water solubilities and
unexpected temperature-dependent phase behavior. In
particular, the transition to heterogeneity instead of a
Acknowledgment
This work was supported by Fundação para a Ciência e a Tecnolo-
gia (PEst-C/LA0006/2011, PTDC/CTM/103664/2008 and a post-
doctoral fellowship GVSMC - SFRH/BPD/72095/2010). The
Figure 1 Chemical-shift variation with temperature in 1H NMR spectra of [DBUH+][(D,L)-Trp] after increasing and decreasing the temperature
(30–90 °C): a) water and presumably primary amine and NH amidine hydrogen bond band; b) protons belonging to CH2 group adjacent to the
amidinium core; c) D,L-tryptophan CH2 protons; d) tryptophan secondary amine proton; e) DMSO peak.
Synlett 2013, 24, 2525–2530
© Georg Thieme Verlag Stuttgart · New York

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Development of Reversible Protic Amino Acid Salts
2529
authors thank Prof. Madalena Dionisio and Dr. Natalia Correia for
support with the DSC analyses.
grade, distilled H2O was processed by Diwer Technologies
water max w2 equipment.
(26) General Procedure for the Preparation of Amino Acid
Based PIL and Ionic Mixtures
Supporting Information for this article is available online at
The organic superbase (1 equiv) diluted in an organic solvent
(1.5–2 mL) was added slowly to a suspension of an amino
acid (1 equiv in 1.5–2 mL of solvent). The resultant mixture
was stirred during a variable period of time at r.t. For
workup, the solvent was evaporated using a rotary
evaporator, and the resultant product was left under high
vacuum for a period of 8–16 h. All the compounds prepared
following this procedure were stored at 7 °C.
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
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C. R. Chimie 2010, 13, 544.
(27) Solubility in Water
To a weighed sample of a salt was added distilled H2O,
dropwise, until homogeneity. The mixture was weighed, and
the proportion of compound to minimum quantity of H2O
was thus obtained.
(28) 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium
2-Aminoacetate {[DBUH][Gly]}
Prepared using the general procedure for the preparation of
amino acid based PIL and ionic mixtures. For the
preparation of this specific compound, the reaction proceeds
over 6 h using MeOH (3 mL) as solvent. After workup the
product was obtained as a heterogeneous white liquid and
solid mixture; yield 89%. 1H NMR (400 MHz, D2O): δ =
1.57–1.62 (m, 6 H), 1.90 (quint, J = 6 Hz, 2 H), 2.50–2.52
(m, 2 H), 3.14 (s, 2 H), 3.21 (t, J = 6 Hz, 2 H), 3.42 (t, J = 6
Hz, 2 H), 3.44–3.46 (m, 2 H) ppm. 13C NMR (100 MHz,
D2O): δ = 18.87, 23.25, 25.81, 28.40, 32.75, 37.91, 43.87,
48.16, 54.10, 165.91, 179.2 ppm. IR (KBr): 3422, 3250,
3119, 2935, 2862, 2623, 2231, 2169, 1647, 1586, 1560,
1476, 1437, 1401, 1366, 1324, 1302, 1270, 1207, 1156,
1126, 1107, 1089, 1043, 1009, 996, 984, 966, 929, 888, 829,
687, 666, 635, 609 cm–1. Anal. Calcd for
(6) Vitorino, J.; Leal, J. P.; Minas da Piedade, M. E.; Canongia
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C11H21N3O2·2H2O): C, 50.17; H, 9.57; N, 15.96. Found: C,
49.58; H, 9.27; N, 16.97.
(29) 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium
(L)-2-Aminopropanoate {[DBUH][ (L)-Ala]}
The reaction proceeded during 24 h at r.t. using MeOH (4
mL) as solvent. After workup the product was obtained as a
white solid; yield 97%. 1H NMR (400 MHz, D2O): δ = 1.12
(d, J = 8 Hz, 3 H), 1.56–1.60 (m, 6 H), 1.88 (quint, J = 4 Hz,
2 H), 2.48–2.51 (m, 2 H), 3.19 (t, J = 6 Hz, 2 H), 3.23 (m, 1
H), 3.40 (t, J = 6 Hz, 2 H), 3.43–3.45 (m, 2 H) ppm. 13
C
NMR (100 MHz, D2O): δ = 18.86, 19.88, 23.25, 25.80,
28.39, 32.73, 37.90, 48.14, 51.29, 54.08, 165.89, 183.65
ppm. IR (KBr): 3397, 3251, 3088, 3000, 2989, 2937, 2863,
2814, 2605, 2505, 2469, 2417, 2294, 2248, 2113, 1653,
1648, 1600, 1521, 1506, 1456, 1413, 1385, 1363, 1320,
1310, 1271, 1237, 1208, 1153, 1115, 1014, 997, 985, 967,
919, 888, 851, 773, 721, 648, 620 cm–1.
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(23) www.iapws.org/relguide/ionization.pdf. Last checked at
28/07/2013; The International Association for the Properties
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H2O, August 2007.
(24) Chaplin, M. Water’s Hydrogen Bond Strength;
http://arxiv.org/ftp/arxiv/papers/0706/0706.1355.pdf.
(25) Reagents and Solvents
(30) 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium
(L)-2-Amino-3-phenylpropanoate {[DBUH][ (L)-Phe]}
The reaction proceeded during 75 h at r.t. using CH2Cl2 (4
mL) as solvent. After workup procedure the product was
obtained as an orange paste; yield 98%. 1H NMR (400 MHz,
D2O): δ = 1.53–1.58 (m, 6 H), 1.85 (quint, J = 6 Hz, 2 H),
2.46–2.47 (m, 2 H), 2.94 (dd, J1 = 12 Hz, J2 = 8 Hz, 1 H),
3.10 (dd, J1 = 16 Hz, J2 = 6 Hz, 1 H), 3.16 (t, J = 4 Hz, 2 H),
3.36 (t, J = 6 Hz, 2 H), 3.40–3.42 (m, 2 H) ppm. 13C NMR
(100 MHz, D2O): δ = 18.85, 23.24, 25.80, 28.39, 32.74,
36.96, 37.90, 48.14, 54.08, 56.20, 127.49, 128.99, 129.33,
135.52, 175.16, 177.49 ppm. IR (KBr): 3426, 3107, 2935,
3258, 3033, 2908, 2883, 2123, 1646, 1560, 1496, 1457,
1410, 1323, 1307, 1207, 1162, 1107, 1075, 984, 913, 848,
746, 699 cm–1. Anal. Calcd for C18H27N3O2·2.6H2O): C,
59.35; H, 8.91; N, 11.54. Found: C, 59.13; H, 8.37; N, 11.11.
Commercial reagents were used as supplied: Glycine was
supplied by BDH with a purity of 99%, L-alanine with a
purity of 99% was provided by Alfa Aesar, L-phenylalanine
purchased from Merck with a purity of >99%, (D,L)-
tryptophan was supplied by Merck with a purity >99%,
1,1,3,3-tetramethylguanidine (TMG), 99%, was supplied by
Sigma-Aldrich and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) ≥99%, was provided by Fluka. Solvents were also
used as supplied: CH2Cl2 was supplied by Sigma-Aldrich,
p.a. grade, MeOH was supplied by Sigma-Aldrich HPLC
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2525–2530

2530
G. V. S. M. Carrera et al.
CLUSTER
123.83, 127.45, 136.28, 165.25, 172.47, 172.51 ppm. IR
(KBr): 3403, 3242, 3106, 3053, 2934, 2861, 2555, 2097,
1719, 1703, 1647, 1608, 1487, 1456, 1404, 1358, 1341,
1320, 1312, 1278, 1229, 1207, 1160, 1106, 1068, 1055,
1008, 995, 984, 965, 914, 900, 877, 864, 845, 834, 766, 746,
738, 720, 691, 660, 625 cm–1. Analysis Calcd for
(31) Bis(dimethylamino)methaniminium (L)-2-Amino-3-
phenylpropanoate {[TMGH][ (L)-Phe]}
The reaction proceeded during 75 h at r.t. using CH2Cl2 (4
mL) as solvent. After workup procedure the product was
obtained as a beige paste; yield 100%. 1H NMR (400 MHz,
D2O): δ = 2.80 (s, 12 H), 2.85 (m, 1 H), 3.00 (dd, J1 = 12 Hz,
J2 = 4 Hz, 1 H), 3.62 (t, J = 6 Hz, 1 H), 7.15–7.27 (m, 5 H)
ppm. 13C NMR (100 MHz, D2O): δ = 38.32, 38.77, 56.63,
127.15, 128.81, 129.34, 136.51, 161.31, 177.81 ppm. IR
(KBr): 3419, 3208, 2964, 2853, 2130, 1609, 1565, 1495,
1456, 1436, 1410, 1340, 1335, 1320, 1307, 1293, 1227,
1163, 1154, 1091, 1073, 1037, 1004, 949, 913, 876, 848,
779, 746, 699, 682, 605 cm–1.
C20H28N4O2·2.4H2O: C, 60.10; H, 8.27; N, 14.02. Found: C,
59.88; H, 7.95; N, 14.28.
(33) Bis(dimethylamino)methaniminium (D,L)-2-Amino-3-
(1H-indol-3-yl)propanoate {[TMGH][(D,L)-Trp]}
The reaction proceeded during 23 h at r.t. using CH2Cl2 (4
mL) as solvent. After workup procedure the product was
obtained as a brown solid; yield 100%. 1H NMR (400 MHz,
DMSO): δ = 2.76 (dd, J1 = 16 Hz, J2 = 8 Hz), 2.84 (s, 12 H),
3.21 (dd, J1 = 16 Hz, J2 = 4 Hz, 1 H), 3.29–3.30 (m, 1 H)
6.93 (t, J = 8 Hz, 1 H), 7.02 (t, J = 8 Hz, 1 H), 7.18 (s, 1 H),
7.32 (d, J = 8 Hz, 1 H), 7.52 (d, J = 8 Hz, 1 H), 11.01 (s, 1
H) ppm. 13C NMR (100 MHz, DMSO): δ = 29.78, 29.80,
55.79, 111.25, 111.37, 117.38, 118.44, 120.62, 123.61,
127.56, 136.29, 161.65, 173.86 ppm. IR (KBr): 3404, 3088,
3056, 2965, 2816, 2742, 2546, 2099, 1718, 1703, 1653,
1608, 1506, 1487, 1456, 1412, 1359, 1341, 1312, 1279,
1232, 1167, 1098, 1068, 1039, 1008, 988, 964, 929, 877,
865, 846, 836, 773, 747, 738, 721, 660, 625 cm–1. Anal.
Calcd for C16H25N5O2·2.2H2O: C, 53.52; H, 8.25; N, 19.51.
Found: C, 53.94; H, 7.56; N, 18.83.
(32) 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium
(D,L)-2-Amino-3-(1H-indol-3-yl)propanoate
{[DBUH][(D,L)-Trp]}
The reaction proceeded during 20 h at r.t. using CH2Cl2 (4
mL) as solvent. After workup procedure the product was
obtained as a yellow solid; yield 100%. 1H NMR (400 MHz,
DMSO): δ = 1.56–1.63 (m, 6 H), 1.85 (quint, J = 6 Hz, 2 H),
2.67–2.70 (m, 2 H), 2.88 (dd, J1 = 16 H, J2 = 8 Hz, 1 H), 3.19
(t, J = 6 Hz, 2 H), 3.25 (m, 1 H), 3.42 (t, J = 6 Hz, 2 H), 3.48–
3.50 (m, 2 H), 6.92 (t, J = 8 Hz, 1 H), 7.03 (t, J = 8 Hz, 1 H),
7.20 (s, 1 H), 7.32 (d, J = 8 Hz, 1 H), 7.53 (d, J = 8 Hz, 1 H),
10.80–11.00 (m, 1 H) ppm. 13C NMR (100 MHz, DMSO):
δ = 18.97, 23.49, 26.04, 28.31, 28.51, 31.22, 37.50, 47.79,
53.18, 54.94, 55.25, 110.46, 111.26, 118.08, 118.43, 120.71,
Synlett 2013, 24, 2525–2530
© Georg Thieme Verlag Stuttgart · New York

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